A clinical study of autologous bone marrow mononuclear cells for cerebral palsy patients: a new frontier

Alok Sharma, Hemangi Sane, Nandini Gokulchandran, Pooja Kulkarni, Sushant Gandhi, Jyothi Sundaram, Amruta Paranjape, Akshata Shetty, Khushboo Bhagwanani, Hema Biju, Prerna Badhe, Alok Sharma, Hemangi Sane, Nandini Gokulchandran, Pooja Kulkarni, Sushant Gandhi, Jyothi Sundaram, Amruta Paranjape, Akshata Shetty, Khushboo Bhagwanani, Hema Biju, Prerna Badhe

Abstract

Cerebral palsy is a nonprogressive heterogeneous group of neurological disorders with a growing rate of prevalence. Recently, cellular therapy is emerging as a potential novel treatment strategy for cerebral palsy. The various mechanisms by which cellular therapy works include neuroprotection, immunomodulation, neurorestoration, and neurogenesis. We conducted an open label, nonrandomized study on 40 cases of cerebral palsy with an aim of evaluating the benefit of cellular therapy in combination with rehabilitation. These cases were administered autologous bone marrow mononuclear cells intrathecally. The follow-up was carried out at 1 week, 3 months, and 6 months after the intervention. Adverse events of the treatment were also monitored in this duration. Overall, at six months, 95% of patients showed improvements. The study population was further divided into diplegic, quadriplegic, and miscellaneous group of cerebral palsy. On statistical analysis, a significant association was established between the symptomatic improvements and cell therapy in diplegic and quadriplegic cerebral palsy. PET-CT scan done in 6 patients showed metabolic improvements in areas of the brain correlating to clinical improvements. The results of this study demonstrate that cellular therapy may accelerate the development, reduce disability, and improve the quality of life of patients with cerebral palsy.

Figures

Figure 1
Figure 1
Improvements in diplegic CP: graph demonstrating symptomatic improvements in diplegic cerebral palsy after cellular therapy.
Figure 2
Figure 2
Improvements in quadriplegic CP: graph demonstrating symptomatic improvements in quadriplegic cerebral palsy after cellular therapy.
Figure 3
Figure 3
Improvements in miscellaneous group of CP: graph demonstrating symptomatic improvements in miscellaneous group of cerebral palsy after cellular therapy.
Figure 4
Figure 4
Improvements in PET-CT scan brain: PET-CT scan images of (A) pre- and (B) postintervention showing increased metabolic activity in various areas. Blue areas indicate hypometabolism, green areas indicate normal metabolism, yellow areas indicate slightly high metabolism, and red areas indicate high metabolism.
Figure 5
Figure 5
Flow chart depicting sequential developmental clinical improvements after autologous BMMNCs transplantation in cerebral palsy. On the left side, there are time periods within which the symptomatic improvements are seen. Each horizontal circle corresponds to the respective time period. The arrows signify direct causal effect between the symptomatic improvements. On the right side, the cognitive improvements are seen to be continuous.

References

    1. Longo M., Hankins G. D. V. Defining cerebral palsy: pathogenesis, pathophysiology and new intervention. Minerva Ginecologica. 2009;61(5):421–429.
    1. Odding E., Roebroeck M. E., Stam H. J. The epidemiology of cerebral palsy: incidence, impairments and risk factors. Disability and Rehabilitation. 2006;28(4):183–191. doi: 10.1080/09638280500158422.
    1. Sophie L. Treatment of Cerebral Palsy and Motor Delay. 5th. Wiley-Blackwell; 2010.
    1. Sharma A., Sane H., Badhe P., et al. Autologous bone marrow stem cell therapy shows functional improvement in hemorrhagic stroke: a case study. Indian Journal of Clinical Practice. 2012;23(2):100–105.
    1. Sharma A., Gokulchandran N., Sane H., et al. Detailed analysis of the clinical effects of cell therapy for thoracolumbar spinal cord injury: an original study. Journal of Neurorestoratology. 2013;1:13–22.
    1. Sharma A., Gokulchandran N., Sane H., et al. Autologous bone marrow mononuclear cell therapy for autism: an open label proof of concept study. Stem Cells International. 2013;2013:13. doi: 10.1155/2013/623875.623875
    1. Sharma A., Sane H., Paranjape A., et al. Positron emission tomography-computer tomography scan used as a monitoring tool following cellular therapy in cerebral palsy and mental retardation—a case report. Journal of Clinical Case Reports. 2013;2013:6. doi: 10.1155/2013/141983.141983
    1. Rosenkranz K., Kumbruch S., Tenbusch M., et al. Transplantation of human umbilical cord blood cells mediated beneficial effects on apoptosis, angiogenesis and neuronal survival after hypoxic-ischemic brain injury in rats. Cell and Tissue Research. 2012;348(3):429–438. doi: 10.1007/s00441-012-1401-0.
    1. Li Y., Tu L., Chen D., Jiang R., Wang Y., Wang S. Study on functional recovery of hypoxic-ischemic brain injury by Rg 1-induced NSCs. Zhongguo Zhongyao Zazhi. 2012;37(4):509–514. doi: 10.4268/cjcmm20120420.
    1. Woodbury D., Schwarz E. J., Prockop D. J., Black I. B. Adult rat and human bone marrow stromal cells differentiate into neurons. Journal of Neuroscience Research. 2000;61(4):364–370. doi: 10.1002/1097-4547(20000815)61:4x0003C;364::aid-jnr2x003E;;2-3.
    1. Sharma A., Sane H., Paranjape A., et al. Positron emission tomography—computer tomography scan used as a monitoring tool following cellular therapy in cerebral palsy and mental retardation—a case report. Case Reports in Neurological Medicine. 2013;2013:6. doi: 10.1155/2013/141983.141983
    1. Carlson R. V., Boyd K. M., Webb D. J. The revision of the Declaration of Helsinki: past, present and future. British Journal of Clinical Pharmacology. 2004;57(6):695–713. doi: 10.1111/j.1365-2125.2004.02103.x.
    1. Folkerth R. D. Neuropathologic substrate of cerebral palsy. Journal of Child Neurology. 2005;20(12):940–949. doi: 10.1177/08830738050200120301.
    1. Volpe J. J. Cerebral white matter injury of the premature infant—more common than you think. Pediatrics. 2003;112(1):176–180. doi: 10.1542/peds.112.1.176.
    1. Hagel C., Stavrou D. Neuropathology of cerebral palsy. In: Panteliadis C. P., Strassburg H. M., editors. Cerebral Palsy: Principles and Management. New York, NY, USA: Thieme; 2004. pp. 49–59.
    1. Miron V. E., Kuhlmann T., Antel Jack J. P. Cells of the oligodendroglial lineage, myelination, and remyelination. Biochimica et Biophysica Acta—Molecular Basis of Disease. 2011;1812(2):184–193. doi: 10.1016/j.bbadis.2010.09.010.
    1. Susuki K. Myelin: a specialized membrane for cell communication. Nature Education. 2010;3(9, article 59)
    1. Hansson E., Rönnbäck L. Glial neuronal signaling in the central nervous system. The FASEB Journal. 2003;17(3):341–348. doi: 10.1096/fj.02-0429rev.
    1. Sharma A., Gokulchandran N., Chopra G., et al. Administration of autologous bone marrow derived mononuclear cells in children with incurable neurological disorders and injury is safe and improves their quality of life. Cell Transplantation. 2012;21(supplement 1):S1–S12.
    1. Mundkur N. Neuroplasticity in children. The Indian Journal of Pediatrics. 2005;72(10):855–857. doi: 10.1007/bf02731115.
    1. Sharma A., Chopra G., Gokulchandran N., Lohia M., Kulkarni P. Autologous bone derived mononuclear transplantation in rett syndrome. Asian Journal of Paediatric Practice. 2011;15(1):22–24.
    1. Sharma A., Gokulchandran N., Badhe P., et al. An improved case of autism as revealed by PET CT scan in patient transplanted with autologous bone marrow derived mononuclear cells. Journal of Stem Cell Research & Therapy. 2013;3, article 139 doi: 10.4172/2157-7633.1000139.
    1. Sharma A., Gokulchandran N., Shetty A., Sane H., Kulkarni P., Badhe P. Autologous bone marrow mononuclear cells may be explored as a novel potential therapeutic option for autism. Journal of Clinical Case Reports. 2013;3(7, article 282) doi: 10.4172/2165-7920.1000282.
    1. Qu S. Q., Luan Z., Yin G. C., et al. Transplantation of human fetal neural stem cells into cerebral ventricle of the neonatal rat following hypoxic-ischemic injury: survival, migration and differentiation. Zhonghua Er Ke Za Zhi. 2005;43(8):576–579.
    1. Chen A., Siow B., Blamire A. M., Lako M., Clowry G. J. Transplantation of magnetically labeled mesenchymal stem cells in a model of perinatal brain injury. Stem Cell Research. 2010;5(3):255–266. doi: 10.1016/j.scr.2010.08.004.
    1. Park K. I., Himes B. T., Stieg P. E., Tessler A., Fischer I., Snyder E. Y. Neural stem cells may be uniquely suited for combined gene therapy and cell replacement: evidence from engraftment of Neurotrophin-3-expressing stem cells in hypoxic-ischemic brain injury. Experimental Neurology. 2006;199(1):179–190. doi: 10.1016/j.expneurol.2006.03.016.
    1. Alvarez P., Carrillo E., Vélez C., et al. Regulatory systems in bone marrow for hematopoietic stem/progenitor cells mobilization and homing. BioMed Research International. 2013;2013:12. doi: 10.1155/2013/312656.312656
    1. Goldman S. A. Progenitor cell-based treatment of the pediatric myelin disorders. Archives of Neurology. 2011;68(7):848–856. doi: 10.1001/archneurol.2011.46.
    1. Brenneman M., Sharma S., Harting M., et al. Autologous bone marrow mononuclear cells enhance recovery after acute ischemic stroke in young and middle-aged rats. Journal of Cerebral Blood Flow and Metabolism. 2010;30(1):140–149. doi: 10.1038/jcbfm.2009.198.
    1. Gnecchi M., Zhang Z., Ni A., Dzau V. J. Paracrine mechanisms in adult stem cell signaling and therapy. Circulation Research. 2008;103(11):1204–1219. doi: 10.1161/CIRCRESAHA.108.176826.
    1. Daadi M. M., Davis A. S., Arac A., et al. Human neural stem cell grafts modify microglial response and enhance axonal sprouting in neonatal hypoxic-ischemic brain injury. Stroke. 2010;41(3):516–523. doi: 10.1161/strokeaha.109.573691.
    1. Pösel C., Möller K., Fröhlich W., Schulz I., Boltze J., Wagner D.-C. Density gradient centrifugation compromises bone marrow mononuclear cell yield. PLoS ONE. 2012;7(12) doi: 10.1371/journal.pone.0050293.e50293
    1. Park H. C., Shim Y. S., Ha Y., et al. Treatment of complete spinal cord injury patients by autologous bone marrow cell transplantation and administration of granulocyte-macrophage colony stimulating factor. Tissue Engineering. 2005;11(5-6):913–922. doi: 10.1089/ten.2005.11.913.
    1. Brenes R. A., Bear M., Jadlowiec C., et al. Cell-based interventions for therapeutic angiogenesis: review of potential cell sources. Vascular. 2012;20(6):360–368. doi: 10.1258/vasc.2011.201205.
    1. Steiner B., Roch M., Holtkamp N., Kurtz A. Systemically administered human bone marrow-derived mesenchymal stem home into peripheral organs but do not induce neuroprotective effects in the MCAo-mouse model for cerebral ischemia. Neuroscience Letters. 2012;513(1):25–30. doi: 10.1016/j.neulet.2012.01.078.
    1. van Praag H., Christie B. R., Sejnowski T. J., Gage F. H. Running enhances neurogenesis, learning, and long-term potentiation in mice. Proceedings of the National Academy of Sciences of the United States of America. 1999;96(23):13427–13431. doi: 10.1073/pnas.96.23.13427.
    1. Colcombe S., Kramer A. F. Fitness effects on the cognitive function of older adults: a meta-analytic study. Psychological Science. 2003;14(2):125–130. doi: 10.1111/1467-9280.t01-1-01430.
    1. Kannan S., Chugani H. T. Applications of positron emission tomography in the newborn nursery. Seminars in Perinatology. 2010;34(1):39–45. doi: 10.1053/j.semperi.2009.10.004.

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